Rapid design and implementation of a virtual pain management programme due to COVID-19: a quality improvement initiative.

Background: The COVID-19 pandemic interrupted the delivery of face-to-face pain services including pain management programmes in the United Kingdom with considerable negative impact on patients with chronic musculoskeletal pain. We aimed to develop and implement a remotely delivered pain management programme (PMP) using video-conferencing technology that contains all the core components of a full programme: the 'virtual PMP' (vPMP). By reporting on the process of this development, we endeavour to help address the paucity of literature on the development of remote pain management programmes. Methods: The vPMP was developed by an inter-disciplinary group of professionals as a quality improvement (QI) project. The Model for Improvement Framework was employed with patient involvement at the design phase and at subsequent improvements. Improvement was measured qualitatively with frequent and repeated qualitative data collection leading to programme change. Quantitative patient demographic comparisons were made with a patient cohort who had been on a face-to-face PMP pathway. Results: Sixty-one patients on the PMP waiting list were contacted and 43 met the criteria for the programme. Fourteen patients participated in three vPMP cycles. Patient involvement and comprehensive stakeholder consultation were essential to a robust design for the first vPMP. Continued involvement of patient partners during the QI process led to rapid resolution of implementation problems. The most prominent issues that needed action were technical challenges including training needs, participant access to physical and technological resources, participant fatigue and concerns about adequate communication and peer support. Conclusion: This report demonstrates how a remotely delivered PMP, fully in line with national guidance, was rapidly developed and implemented in a hospital setting for patients with chronic musculoskeletal pain. We also discuss the relevance of our findings to the issues of cost, patient experience, patient preferences and inequities of access in delivering telerehabilitation for chronic pain.

Dual neutralisation of IL-17F and IL-17A with bimekizumab blocks inflammation-driven osteogenic differentiation of human periosteal cells.

OBJECTIVES: Interleukin (IL)-17 signalling has been shown to be a key regulator of disease in ankylosing spondylitis (AS) with several IL-17 blockers currently clinically approved. Despite this, the role of IL-17 in bone pathology is poorly understood. This study aimed to investigate IL-17 signalling in the context of pathological bone formation. METHODS: A biomimetic human periosteum-derived cell (hPDC) model of osteogenic differentiation was used in combination with recombinant IL-17 cytokines, T-cell supernatants or serum from patients with AS. IL-17A, IL-17F and bimekizumab monoclonal antibodies were used to block IL-17 cytokine action. RESULTS: Recombinant IL-17A and IL-17F are pro-osteogenic with respect to hPDC differentiation. T helper 17 or γδ-T cell supernatants also potently stimulated in vitro bone formation, which was blocked deeper by dual inhibition of IL-17A and IL-17F than by neutralisation of IL-17A or IL-17F individually. Osteogenic blockade may be due to an increase in expression of the Wnt antagonist DKK1. Interestingly, osteocommitment was also induced by serum obtained from patients with AS, which was also abrogated by dual neutralisation of IL-17A and IL-17F. CONCLUSIONS: These data show for the first time that IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from hPDCs, inhibition of which may offer an attractive therapeutic strategy to prevent pathological bone formation.

Latency can be conferred to a variety of cytokines by fusion with latency-associated peptide from TGF-ß.

OBJECTIVES: Targeting cytokines to sites of disease has clear advantages because it increases their therapeutic index. We designed fusion proteins of the latent-associated peptide (LAP) derived from TGF-ß with various cytokines via a matrix metalloproteinase (MMP) cleavage site. This design confers latency, increased half-life and targeting to sites of inflammation. The aim of this study is to determine whether this approach can be applied to cytokines of different molecular structures and sizes. METHODS: Mature cytokines cloned downstream of LAP and a MMP cleavage site were expressed in 293T cells and assessed for latency and biological activity by Western blotting and bioassay. RESULTS: We demonstrate here that fusion proteins of TGF-ß, erythropoietin, IL-1ra, IL-10, IL-4, BMP-7, IGF1 and IL-17 were rendered latent by fusion to LAP, requiring cleavage to become active in respective bioassays. As further proof of principle, we also show that delivery of engineered TGF-ß can inhibit experimental autoimmune encephalomyelitis and that this approach can be used to efficiently deliver cytokines to the brain and spinal cord in mice with this disease. CONCLUSIONS: The latent cytokine approach can be successfully applied to a range of molecules, including cytokines of different molecular structure and mass, growth factors and a cytokine antagonist.

Latent cytokines for targeted therapy of inflammatory disorders.

INTRODUCTION: The use of cytokines as therapeutic agents is important, given their potent biological effects. However, this very potency, coupled with the pleiotropic nature and short half-life of these molecules, has limited their therapeutic use. Strategies to increase the half-life and to decrease toxicity are necessary to allow effective treatment with these molecules. AREAS COVERED: A number of strategies are used to overcome the natural limitations of cytokines, including PEGylation, encapsulation in liposomes, fusion to targeting peptides or antibodies and latent cytokines. Latent cytokines are engineered using the latency-associated peptide of transforming growth factor-ß to produce therapeutic cytokines/peptides that are released only at the site of disease by cleavage with disease-induced matrix metalloproteinases. The principles underlying the latent cytokine technology are described and are compared to other methods of cytokine delivery. The potential of this technology for developing novel therapeutic strategies for the treatment of diseases with an inflammatory-mediated component is discussed. EXPERT OPINION: Methods of therapeutic cytokine delivery are addressed. The latent cytokine technology holds significant advantages over other methods of drug delivery by providing simultaneously increased half-life and localised drug delivery without systemic effects. Cytokines that failed clinical trials should be reassessed using this delivery system.

Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients with early rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) is an important mediator of cachexia, and its blockade prevents catabolism in animal models. However, little evidence shows that anti-TNF therapy is effective in treating cachexia in humans. OBJECTIVE: The main aim of this study was to investigate the effect of etanercept, a synthetic soluble TNF receptor, on body composition in patients with early rheumatoid arthritis (RA). DESIGN: Twenty-six patients were randomly assigned to 24 wk of treatment with etanercept or methotrexate; the latter is the first-line therapy for RA. Body composition, physical function, disease activity, systemic inflammation, and the circulating insulin-like growth factor (IGF) system were measured at baseline (week 0) and at follow-up (weeks 12 and 24). Twelve patients in each treatment group (9 F, 3 M) completed the study. RESULTS: Overall, no important changes in body composition were observed, despite a transient increase in IGF-I at week 12 (P < 0.01). However, the secondary analysis of those patients (6/treatment group) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained: 44% of weight gained in the etanercept group was fat-free mass, as compared with only 14% in the methotrexate group (P = 0.04). Etanercept and methotrexate were equally effective in controlling the disease and improving physical function. CONCLUSIONS: Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo. However, TNF blockade seems to normalize the anabolic response to overfeeding and, if these findings are confirmed, may be useful in conditions characterized by anorexia and weight loss.

Primary vasculitis at high altitude.

We describe a 34-year-old mountaineer who presented with gut infarction from necrotizing vasculitis, probably due to Churg-Strauss syndrome. Subsequently, relapses occurred whenever he climbed to 4000 meters. We hypothesize that the effects of vasculitis were compounded by the physiological changes at high altitude. We suggest that patients with systemic vasculitis should be cautious about climbing and trekking at high altitude.

Ultrasonography in the diagnosis and follow-up of idiopathic inflammatory myopathies--a preliminary study.

OBJECTIVE: To study the utility of ultrasonography (US) in diagnosis and follow up of patients with idiopathic inflammatory myopathy (IIM). METHODS: High-resolution US of thigh muscles was recorded at baseline and after six months of treatment in eleven patients of early, active, untreated IIM. Parameters studied were muscle power, timed function tests (TFT), muscle enzymes, electromyography, muscle histopathology and US parameters such as echogenicity of muscle and perimysial septa count per 1 cm muscle width. RESULTS: There was a significant increase in muscle echogenicity and septa count of patients as compared to those of controls (p = 0.002 and 0.00003, respectively). These abnormalities resolved on treatment. Muscle echogenicity and perimysial septa count showed mild positive correlation with walking time, 4-step climbing and myopathic pattern on EMG. Perimysial septa count in addition correlated weakly with creatine phosphokinase, lactate dehydrogenase and muscle fibre necrosis. CONCLUSION: US seems to be a useful, non-invasive, cheap modality to monitor the disease course in IIM. Larger studies to confirm these primary findings are warranted.

A longitudinal study of serum creatinine levels in patients of rheumatoid arthritis on long term NSAID therapy.

AIM: Primary: To study the effect of long term NSAID therapy on serum creatinine in patients of rheumatoid arthritis. Secondary: To study the effect of discontinuation, reduction in the dose or continuation of NSAID and of rechallenge. MATERIAL AND METHODS: Case records of RA patients with a minimum two years of follow up were analysed. Age, sex, duration of RA, type, dose and duration of NSAID and DMARD therapy, co-morbid conditions and serial serum creatinine levels were charted. RESULTS: Ninety nine case records were studied. Incidence of abnormal creatinine level (renal insufficiency) defined as rise in creatinine equal to or above the upper limit of normal was 27.7%. This rise was asymptomatic in all patients. No NSAID was particularly associated with an increased risk in renal insufficiency. The rise of serum creatinine was reversible in most patients irrespective of discontinuation or continuation of NSAID but settled at a higher level. Rechallenge resulted in rise of serum creatinine in 50% patients. Hypertension, DM, IHD and diuretics carried a higher but not statistically significant risk of renal insufficiency. CONCLUSION: NSAID-induced asymptomatic rise of creatinine in patients of RA on long term NSAIDs is common. It is mostly reversible. Regular monitoring of serum creatinine is essential.